Efficacy and safety of pinaverium bromide as an add‐on therapy in refractory dyspepsia: A randomized controlled trial

Abstract Background and Aim Functional dyspepsia (FD) remains a therapeutic challenge, and the efficacy of antispasmodic agents as adjunctive therapy is not well established. This study aimed to evaluate the efficacy and safety of pinaverium bromide added to omeprazole in treating refractory FD. Methods We conducted a randomized, placebo‐controlled trial in patients with refractory dyspepsia. Participants were randomly assigned to receive pinaverium (50 mg, 3 times/day, n = 36) or placebo (n = 36) in addition to omeprazole for 8 weeks. The primary endpoint was the responder rate for adequate relief. Secondary outcomes included the Global Overall Symptom Scale (GOSS), quality of life, and safety profile. Results No statistically significant differences were observed in the adequate relief response rate between the pinaverium bromide and control group at week 2 (58.3% vs. 62.9%, P = 0.697), week 4 (62.9% vs. 78.1%, P = 0.173), week 6 (64.7% vs. 75.0%, P = 0.363), and week 8 (64.7% vs. 75.0%, P = 0.363). Additionally, there were no significant differences observed in the decline of symptom score between the two groups at week 4 (8.4 ± 7.6 vs. 7.7 ± 7.1, P = 0.702) and week 8 (10.9 ± 8.2 vs. 8.4 ± 7.2, P = 0.196). Similarly, there were no significant differences in terms of quality of life between the two groups. Adverse event rates were also comparable between the two groups. Conclusion Pinaverium bromide was found to be safe in the treatment of refractory dyspepsia, but it did not demonstrate a significant benefit in improving symptoms.


Introduction
Functional dyspepsia (FD) is a prevalent gastrointestinal disorder with a worldwide prevalence of 6.9% by ROME IV criteria. 1he condition is characterized by two subtypes: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which may overlap. 2 Despite its benign nature, FD often causes unpleasant symptoms that affect patients' physical, psychological, social, and economic well-being. 3roton pump inhibitors (PPIs) are currently considered firstline therapy according to current guidelines. 4,57][8][9] Despite the availability of new treatment options with alternative mechanisms of action, the evidence supporting their use remains limited.
Duodenal low-grade inflammation has been proposed as a potential pathogenesis of FD.Several studies have demonstrated an increase in eosinophils and mast cells in the duodenal tissue of FD patients. 10,11This inflammation may lead to decreased mucosal integrity and abnormal smooth muscle contractions. 12,13revious research from our group has shown that a combination of antispasmodic and anxiolytic drugs (clidinium bromide/chlordiazepoxide) improves symptoms and quality of life in FD patients refractory to PPIs. 14However, the effect of antispasmodic monotherapy as an add-on treatment to PPIs in FD remains undefined.
Pinaverium bromide is an antispasmodic drug acting on a muscarinic receptor with high safety profile.We hypothesize that adding pinaverium bromide to a PPI might assist the treatment in PPI-resistant dyspepsia.Therefore, we conducted a randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety profile of pinaverium bromide add-on to PPI in FD patients who had incomplete response to PPI therapy.

Methods
Study design.This study was a single-center, double-blind, randomized controlled trial carried out at Chiang Mai University Hospital from June 2021 to August 2022, in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.All patients provided written informed consent prior to participation.The study was approved by the Institutional Review Board (MED-2563-07700) and registered with the Thai Clinical Trials Registry (TCTR20210819002).
Participants.We included patients aged 18-70 years who met the Rome IV criteria for a diagnosis of FD and had persistent symptoms despite receiving a standard dose of PPIs for at least 8 weeks before enrollment.Additionally, all patients had normal results from upper endoscopy and tested negative for Helicobacter pylori infection within the 3 years prior to enrollment.
We excluded patients who met any of the following criteria: (a) concurrent diagnosis of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), or defecation problems; (b) presence of severe comorbidities or end-stage renal disease; (c) pregnancy or breastfeeding or had planned pregnancies; (d) known history of allergies to pinaverium bromide or PPIs.Additionally, any patient currently taking nonsteroidal antiinflammatory drugs was also excluded from the study.
Randomization and intervention.Computer-generated blocking randomization was used for patients' randomization to receive either pinaverium or placebo add-on to standard dose omeprazole.An independent staff member assigned the treatments according to consecutive numbers, which were kept in sealed envelopes.All investigators and patients were blinded to treatment allocation.
Eligible patients had a 2-week drug washout period including PPIs, prokinetics, simethicone, alginate, and antispasmodic drugs before starting the study medication.Then, patients were randomly assigned to receive either pinaverium bromide (Dicetel ® , Abbott Inc.) (50 mg, 3 times/day) or placebo (identical starch-containing capsule) add-on to standard dose omeprazole (20 mg once daily) for 8 weeks.During the study, the participants were advised to avoid using over-the-counter medication.An antacid was given as rescue medicine.Compliance was checked by pill count at week 4 and week 8.

Data collection and outcome assessment
Data collection.Baseline characteristics were recorded including age, gender, medical illness, psychiatric condition, FD subtype by Rome IV criteria, the Hospital Anxiety and Depression Scale (HADS), 15 FD specific Global Overall Symptom Scale (GOSS), and quality of life.Self-report of adequate relief was recorded in the given diary; patients were noted whether they were satisfied with the symptom relief or not by answering 'yes or no' every day in their diary during 8-week study period.Patients were considered as a responder if they reported adequate relief over 50% of days during the period of treatment.Dyspeptic symptom score was assessed using a GOSS 16 (using the 7-point Likert dyspepsia severity scale) every 4 weeks.The quality of life was assessed using the short-form Nepean Dyspepsia Index 17 at baseline and post-treatment.The translation of questionnaire had undergone the forward-backward translation method by the language institute Chiang Mai University and assessed by three independent gastroenterologists for content validity and clarification of the language.The short-form Nepean Dyspepsia Index comprises of five subcategories: interference, knowledge/control, eating/drinking, sleep disturbance, work/study, and scores, summarized into an overall quality of life score ranging from 10 to 50.Higher scores on the GOSS and short-form Nepean Dyspepsia Index indicated more severe symptoms and a lower quality of life, respectively.
Outcomes and definitions.The primary outcome, the adequate relief response rate, was defined as the proportion of patients reporting satisfactory symptom relief on more than 50% of days during the treatment period.Secondary outcomes included improvement in quality of life as measured by the short-form Nepean Dyspepsia Index, changes in overall symptom scores on the GOSS, and the safety profile assessed through the incidence of adverse events.

Statistical analysis.
According to previous research, 18 the power calculation assumed of 40% responder in the placebo arm.As this was the first study of pinaverium bromide in FD patients, based on therapeutic gain of the clidinium/chlordiazepoxide in FD, 14 we expect a 35% therapeutic gain over placebo.The sample size calculation used an estimate of 40% responders in the placebo group and 75% responders in the treatment group with a 5% α-error and a 20% β-error; assuming a 20% drop-out rate, the trial required at least 36 patients in each arm.
The primary outcome was analyzed based on the intention-to-treat analysis.Chi-square test or Fisher's exact test was used to evaluate the difference between the two treatment arms in terms of the proportion of responders, and the rates of adverse events.The dyspepsia symptom score and quality of life scores were compared between the two treatment arms using an independent t-test or Mann-Whitney U test as appropriate.All statistical analyses were performed using Stata (version 16.0 for Windows, StataCorp LCC).A P-value less than 0.05 was considered a statistically significant difference.

Results
Baseline characteristics.One-hundred and seven outpatients with the diagnosis of FD were screened.Of these, The baseline characteristics of the two groups were comparable, except for BMI, which was slightly higher in the pinaverium group (mean of 24.1 AE 3.0 vs. 22.4 AE 2.9, P = 0.012).Six patients (8.3%) dropped out of the study, four from the pinaverium group, and two from control group.A total of 66 patients completed the trial, 32 in the treatment group and 34 in the control group (Fig. 2).The overall compliance was greater than 90% for all participants.
Self-report of adequate relief.According to ITT analysis, there was no significant difference in the primary outcome, rate of responders, between the pinaverium group and the placebo group at various time points throughout the 8-week treatment period (58.2% vs. 62.9% at week 2, 62.9% vs. 78.1% at week 4, 64.7% vs. 75.0%at week 6, and 64.7% vs. 75.0%at week 8) (Fig. 3).No notable variations were observed when results were analyzed using per-protocol analysis.
Quality of life.Baseline SF-NDI scores for overall quality of life and the five subscales were comparable between two groups.After 8 weeks of treatment, there was no significant difference in the decrease of SF-NDI scores between the two groups.(Table 3).
Safety profile.There were 14 reported adverse events in the trial, with no significant difference in rate between the pinaverium and control groups (27.8% vs. 47.2%, respectively; P = 0.088).The most common side effects were dizziness and epigastric burning (Table 4).Four patients in pinaverium group did not complete the study due to adverse events (two epigastric burning, two abdominal pain).There were no serious adverse events during the 8 weeks of study.

Discussion
This randomized placebo-controlled trial aimed to assess the efficacy and safety of pinaverium bromide as an add-on to omeprazole for the treatment of refractory dyspepsia.The study found no statistically significant differences in the primary endpoint of adequate relief response rate between the pinaverium bromide and placebo groups.Additionally, there were no significant differences observed in the secondary outcomes, such as the Global Overall Symptom Scale (GOSS) and quality of life, between the two groups.
In this study, the responder rate in the control group was found to be around 60%, which is higher than the placebo response rate reported in other studies 19,20 and our previous research. 14,19This high placebo response rate may be attributed to the effect of omeprazole given in the control group.Even though we only enrolled PPI nonresponsive patients, some participants may have previously received non-omeprazole PPI, which could have caused a PPI switching effect.Additionally, the discontinuation of PPI during the washout period and the reintroduction of PPI may have also improved the participants' symptoms.Furthermore, all participants underwent upper endoscopy and ultrasonography before enrollment, which may have reduced their stress and anxiety, leading to an increased placebo response rate in the study.
Clidinium/Chlordiazepoxide, a combination of antispasmodic and anxiolytic drugs, has been shown to be beneficial in dyspepsia in our previous study. 14However, in this study, pinaverium bromide, a pure anti-spasmodic drug, failed to show the same results.Our results suggest that the patients in the clidinium/chlordiazepoxide study might respond mainly on the effect of anxiolytic effect over antispasmodic effect.
FD is composed of complex pathophysiology.1][12][13] Our results suggest that the modulation of abnormal intestinal contraction may not be beneficial for all patients with FD.However, subtype analysis revealed improvement in early satiety, a common symptom of PDS.It is known that duodenal inflammation is prominent in FD patients with post-prandial distress syndrome. 21Therefore, further research is needed to explore the potential benefits of antispasmodics in this specific subgroup of FD patients.
There are several strengths of our study.To the best of our knowledge, this is the first randomized controlled trial to study the effect of anti-spasmodic in refractory FD patients.Strict inclusion criteria were applied, including Rome IV criteria and significant symptoms impacting quality of life.Both upper endoscopy and upper abdominal ultrasonography were conducted to exclude organic diseases.Additionally, strict exclusion criteria were applied to minimize overlap with other functional gastrointestinal disorders, specifically IBS, for precise outcome assessment.
Our study has several limitations that must be taken into account when interpreting the results.The first limitation is the potential lack of generalizability due to the study's single-center, university referral hospital setting.Additionally, the small sample size may have resulted in the study being underpowered to detect a real treatment effect.This should be considered when interpreting the results and interpreting the lack of significant differences in the primary and secondary outcomes.Furthermore, the study design did not include an assessment of gastrointestinal motility via physiological testing or duodenal biopsy to evaluate for the presence of inflammation, which could have further provided more insights into the results.
Despite these limitations, the study still provides important information on the safety profile of pinaverium bromide in this population and can serve as a basis for future research.Future studies should consider increasing the sample size and incorporating these assessments in order to enhance the power of the study and better understand the potential benefit of pinaverium bromide in the treatment of refractory dyspepsia.
In conclusion, our study found no significant benefit of adding pinaverium bromide, an anti-spasmodic drug, to PPI for treating refractory FD.Despite these findings, the drug demonstrated a good safety profile with no serious adverse effects.Further research with larger sample sizes is necessary to confirm these findings and explore potential benefits in specific subgroups.

Figure 3
Figure 3 Rate of responders (self-report of adequate relief, %) between groups by intention-to-treat analysis.pinaverium; , control.

Figure 4
Figure 4 Mean difference in global overall symptom scale between groups.pinaverium;, placebo.

Table 2
Secondary outcome showing seven-point global overall symptom scale between groups, mean AE SD

Table 3
Secondary outcome showing the short-form Nepean Dyspepsia Index between groups, mean AE SD

Table 4
Adverse event between groups